The Role of Heliox in Respiratory Control (DEPSCoR)

Optimizing Mind-Body Interactions in Respiratory Control During Operationally Relevant Environmental Stressors

Warfighters are frequently exposed to environments and life-support systems that increase breathing resistance and the work of breathing (WOB), such as aircraft on-board oxygen generation systems and underwater breathing apparatuses. Elevated WOB increases the perception of breathing difficulty (dyspnea) and has been associated with impaired cognitive performance, including slower reaction time and reduced accuracy during attention-demanding tasks. These effects are particularly concerning in operational settings that require rapid decision-making and precise motor responses.

Despite growing recognition of this issue, critical gaps remain regarding strategies to mitigate the perceptual and cognitive consequences of elevated inspiratory resistance, especially under realistic operational stressors. The objective of this study is to determine whether reducing mechanical WOB alters breathing perception and cognitive performance during inspiratory resistance. Participants will breathe either normal-density air or a low-density helium-oxygen gas mixture (heliox) to determine whether reducing mechanical WOB lowers perceived breathing effort and improves cognitive function.

Study Overview

• Status: Recruiting
• Conditions: Work of Breathing
• Intervention / Treatment: Drug: Heliox inspirate

Detailed Description

Increases in the WOB intensify the sensory and emotional perceptions of dyspnea, at least partly due to heightened conscious awareness of breathing. Recent data indicate that elevated WOB, and likely breathing perception, can impair cognitive function. This impairment is likely caused by negative affective sensations resulting from the increased WOB, which distracts from central information processing during complex reaction-time tasks. Additionally, both reaction time and accuracy worsen when greater loads are placed on the inspiratory muscles. However, several key knowledge gaps remain that are pertinent to Warfighters that experience elevated inspiratory resistance. This study will investigate whether reducing the WOB during inspiratory resistance can lower breathing perception and restore cognitive function.

Heliox lowers the resistive WOB and muscle load because of its low density and viscosity, allowing for higher ventilation rates than room air by reducing turbulent flow in the airways. Therefore, breathing heliox, which will lower the WOB, under high inspiratory resistance will provide critical insights into whether reducing the WOB can improve cognitive function. It's hypothesized that using heliox will decrease the WOB, lower perceived breathing effort, and improve cognitive function compared to breathing normal density air with elevated inspiratory resistance.

Participants will complete two study visits: a screening/familiarization visit (Study Day 0) followed by one experimental visit (Study Day 1). Participants will be instructed to avoid caffeine, alcohol, stimulant medication, pain/anti-inflammatory medication, cannabis and cannabis related products, and vigorous exercise for at least 24 hours prior to experimental visits. On Study Day 0, participants will complete a short familiarization breathing task in which they will breathe for 10 minutes through an 8-10mm hole at the end of a customized device, generating a pre-determined inspiratory resistance of 6-9.5 centimeters of water per liter per second (cmH2O/L/s). During the breathing task, cerebral vascular, cardiovascular and autonomic activity responses will be measured. Every 5 minutes during the breathing test, participants will be asked to rate breathing intensity and unpleasantness, and perform an inspiratory capacity maneuver. Cognitive assessments will be administered every10 minutes. After the breathing task, participants will complete lung and respiratory muscle function tests.

Prior to Study Day 1 (the experimental visit), participants will be randomized to the order in which they are exposed to the interventional conditions (room air or heliox). Upon arrival, an esophageal balloon will be placed to measure the pressure around the heart and lungs. Participants will then complete two full-length breathing tasks, in which they inspire against a predetermined resistive load for 60 minutes, while breathing under the assigned conditions in the order of randomization. Biometric monitoring, cognitive tasks and participant ratings during the breathing tasks will be completed with the same frequency as Study Day 0. A 1-hour rest period will be observed between the breathing tasks.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Timothy D Mickleborough, PhD; Phone Number: 812-855-0753; Email: tmickleb@iu.edu

Study Locations

• United States
  • Indiana
    • Bloomington, Indiana, United States, 47405
      • Recruiting
      • Multidisciplinary Engineering and Sciences Hall (MESH)
      • Contact: Scott M Clarke; Phone Number: 812-856-3244; Email: scotclar@iu.edu
      • Contact: Zachary J Schalder, PhD; Phone Number: 812-855-6953; Email: zschlade@iu.edu
      • Principal Investigator: Timothy D Mickleborough, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Between the ages of 18-40 years old.
• English speaking and reading.
• Self-reported weekly activity of at least 120 minutes/week of high intensity exercise for the previous 2 years.
• Normal pulmonary function assessed by a resting forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) > 75% of predicted.
• Normal cognitive function assessed using the Montreal cognitive function test [18].
• Body mass index (BMI) ≤ 35 kg/m2.
• Females with a regular menstrual cycle that ranges from 21-35 days (eumenorrhea)

Exclusion Criteria:

• History of smoking or recreational smoking, cardiovascular disease, renal disease, pulmonary disease (including asthma or exercise-induced asthma), neurological disease, and metabolic disease.
• Are pregnant or could possibly be pregnant by self-report.
• Are color blind.
• Known allergy or hypersensitivity latex.
• Take selective serotonin reuptake inhibitors, stimulant medication, antibiotics, and chronically consume pain medication (Aleve, Tylenol, etc.).
• Resting blood pressure of > 130mmHg systolic or 90 mmHg diastolic and/or resting pulse rate of > 100 bpm.
• Females with irregular menstrual cycles (oligomenorrhea) that ranges from 36-90 days, and females with the absence of a menstrual cycle (amenorrhea).
• Taking birth control for the sole purpose of period cessation (eg., Mirena IUD)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Room Air, then Heliox Inspirate; Participants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization.	Drug: Heliox inspirate; This intervention corresponds to Arm 1 titled "room air and heliox inspirate". This corresponds with the first phase/period of this study.
Active Comparator: Heliox Inspirate, then Room Air; Participants will complete 2 full length breathing tasks, one under each condition. The order of condition exposure will be assigned via randomization.	Drug: Heliox inspirate; This intervention corresponds to Arm 1 titled "room air and heliox inspirate". This corresponds with the first phase/period of this study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Stroop Color-Word Test Time Performance	Time performance on the Stroop Color-Word Test (min:sec) will be measured every 10 minutes during each breathing task.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Stroop Color-Word Test Error Performance	The number of errors on the Stroop Color-Word Test will be measured will be measured every 10 minutes during each breathing task.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Perception of Dyspnea Intensity	Participants will rate perception of dyspnea (breathing) intensity on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line (100mm),indicating their breathing perception from "not noticeable" (0mm) to "maximal imaginable intensity" (100mm).	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Perception of Dyspnea Unpleasantness	Participants will rate perception of dyspnea (breathing) unpleasantness on a visual analog scale (VAS) every 5 minutes during each breathing task. The participant will draw a vertical marker line on a horizontal line(100mm), indicating their breathing perception from "not unpleasant"(0mm) to "maximal imaginable unpleasantness" (100mm).	Before and after each Day 1 breathing task (approximately 60 minutes in duration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Work of Breathing - Esophageal Pressure	Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via esophageal balloon pressures during the heliox condition.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Mouth Pressure	Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via esophageal balloon pressures, mouth pressure, and dynamic lung volumes during the heliox condition.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Work of Breathing - Dynamic Lung Volume	Heliox-induced reduction in WOB will be summarized by pre- and post-values of pressure (unit: cmH2O) via dynamic lung volumes during the heliox condition.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Velocity	Bilateral transcranial Doppler Ultrasound will be used to continuously measure middle and posterior cerebral artery blood velocity during each breathing task. The ultrasound transducers will be placed on both sides of the head at the temporal windows and the positions will be fixed using a transducer holder.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Cerebral Blood Oxygen Kinetics	Oxyhemoglobin and deoxyhemoglobin (uptake/extraction, uM) will be measured continuously via near-infrared spectroscopy (NIRS) of the pre-frontal cortex during each breathing task.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Heart Rate	Heart Rate will be measured continuously during each breathing task by 3-lead electrocardiograph (ECG).	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Finger Photoplethysmography	Blood pressure will be measured continuously during each breathing task via finger photoplethysmography.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)
Change in Blood Pressure - Brachial Artery	Blood pressure will be measured every 10 minutes during each breathing task via a standard blood pressure cuff and auscultation of the brachial artery.	Before and after each Day 1 breathing task (approximately 60 minutes in duration)

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: United States Department of Defense

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2026
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: December 18, 2025
• First Submitted That Met QC Criteria: February 19, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Cognitive Performance; Inspiratory Resistance; Dyspnea Perception
• Additional Relevant MeSH Terms: Environment and Public Health; Physical Phenomena; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Thermodynamics; Weather; Atmosphere; Meteorological Concepts; Temperature; Hot Temperature
• Other Study ID Numbers: 28381 - Aim 1; FOAAFRLAFOSR20240007 (Other Grant/Funding Number: Air Force Office of Scientific Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The plan to share individual participant data (IPD) is still unknown. However, if other researchers request IPD, we will evaluate that request and determine to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes